The overall goal of this program project continues to be the development of a rational treatment program for nephrolithiasis, in which the chosen treatment corrects underlying derangements and prevent new stone formation without causing complications. Much progress has been made: (a) a diagnostic protocol capable of elucidating the cause of stone disease in more than 95% of patients has been developed, (b) the work under this program project resulted in development of sodium cellulose phosphate, potassium citrate and MPG. In this renewal, further pathophysiologic and therapeutic explorations are planned: (a) the importance of 1,25-(OH)2D in absorptive hypercalciuria will be examined by receptor binding and RFP, as well as by antagonism of 1,25-(OH)2D action by 25,26-(OH)2D; (b) the renal contribution of hypocitraturia will be evaluated using rat tubular microperfusion as well as by measurement of renal tissue pH in vivo; (c) the intestinal contribution to hypocitraturia will be explored from the correlation of net gastrointestinal absorption of alkali with urinary citrate, and from direct measurement of intestinal citrate absorption; (d) adverse physiological consequences of lithotripsy will be critically assessed; (e) extra-renal sequelae of long-term medical treatments will be quantitated; and (f) therapeutic potential of potassium-magnesium citrate and 25,26-(OH)2D will be investigated.